Atorvastatin calcium is known by synonyms like [R—(R*,R*)]-2-(4-fluorophenyl)-□□, 6-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyy-1h-pyrrole-1-heptanoic acid hemicalcium salt; (□R,□R)-2-(4-fluorophenyl)-□□-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-, 1H-Pyrrole-1-heptanoic acid hemicalcium salt; [R—(R*,R*)]-2-(4-fluorophenyl)-□□-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-, 1H-Pyrrole-1-heptanoic acid hemicalcium salt or (□R,□R)-2-(p-Fluorophenyl)-□□-dihydroxy-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrole-1-heptanoic acid hemicalcium salt.
Hemicalcium salt of [R—(R*,R*)]-2-(4-fluorophenyl)-□□-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-, 1H-Pyrrole-1-heptanoic acid, a synthetic HMG-CoA reductase inhibitor, is used for the treatment of hyperlipidemia and hypercholesterolemia, both of which are risk factors for arteriosclerosis and coronary heart disease. Open dihydroxy carboxylic acid, lactone and various salt forms of [R—(R*,R*)]-2-(4-fluorophenyl)-□□-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-, 1H-Pyrrole-1-heptanoic acid have been synthesized.
U.S. Pat. No. 5,273,995, describes that [R—(R*,R*)]-2-(4-fluorophenyl)-□□-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-, 1H-Pyrrole-1-heptanoic acid has surprising inhibition of the biosynthesis of cholesterol. Calcium salt of [R—(R*,R*)]-2-(4-fluorophenyl)-□□-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-, 1H-Pyrrole-1-heptanoic acid (2:1) which is more suited to formulations and has been recommended as a drug.
U.S. Pat. Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,273,995; 5,280,126; 5,298,627; 5,342,952; 5,385,929; 5,397,792; European Patent 409,281; and WO 89/07598 describe various processes and key intermediates for preparing atorvastatin.
WO 97/03958 and WO 97/03959 disclose novel crystalline forms of atorvastatin calcium designated as Form I, Form II, Form III and Form IV and method for their preparation which provide more favorable filtration and drying characteristics.
WO 97/03960 and U.S. Pat. No. 6,087,511 describe the procedures for converting the crystalline form of atorvastatin calcium to the amorphous form. The process disclosed therein involve dissolving form I atorvastatin calcium in a non-hydroxylic solvent like tetrahydrofuran or a mixture of tetrahydrofuran and toluene.
WO 00/71116 describes the procedure for converting the crystalline form-I by dissolving it in a non-hydroxylic solvent like tetrahydrofuran and precipitating amorphous atorvastatin calcium by the addition of nonpolar hydrocarbon solvents like, n-hexane, cyclohexane or n-heptane. The process described in the above mentioned patent involves dissolving the crystalline atorvastatin (form-I) in a non hydroxylic solvent like tetrahydrofuran or mixtures of tetrahydrofuran and toluene, followed by removal of the solvents under high temperature (about 90° C.) and high vacuum (about 5 mm). This process may not suitable on a large scale as the conditions used for drying may lead to degradation of the product.
Many of the process disclosed in the above patents does not produce atorvastatin calcium in its amorphous form consistently. Often a mixture of crystalline and amorphous form is obtained which is not suitable for filtration and drying and therefore not a desirable process for large-scale production.
It is the object of the present invention to provide a novel process for the preparation of amorphous atorvastatin calcium, which is unique with respect to its simplicity, cost effectiveness and scalability.